The Section on Developmental Genetics conducts both laboratory and clinical investigations to understand the molecular mechanisms of heritable neurodegenerative lysosomal storage disorders (LSDs) that primarily affect children. As a group, these disorders represent the most common (1 in 12,500 births) neurodegenerative LSDs and are called neuronal ceroid lipofuscinoses (NCLs), commonly known as Batten disease. Mutations in 8 different genes are reported to cause various forms of Batten disease. There is no effective treatment for any of these diseases. Currently, our investigations are focused on understanding the molecular mechanism(s) of infantile form of NCL or INCL, which is one of the most lethal and devastating disease. The children with INCL are normal at birth but by 11-18 months of age they develop psychomotor retardation and complete retinal blindness. By age four years these children manifest no brain activity. They remain in a vegetative state for another 6-8 yars before death. Our long-term goals are to utilize the knowledge gained from laboratory investigations to develop novel and effective therapeutic approaches to these diseases. Our laboratory investigations on INCL have led to a bench-to-bedside clinical trial, which is currently ongoing. Recently, using Ppt1-knockout (Ppt1-KO) mice that recapitulate virtually all clinical and pathological features of INCL, we uncovered for the first time that PPT1-deficiency leads to endoplasmic reticulum (ER) and oxidative stresses leading to neuronal death. In addition we discovered that PPT1-deficiency disrupts synaptic vesicle recycling and regeneration causing a progressive decline in the synaptic vesicle (SV) pool, which leads to abnormal neurotransmission, characteristic of INCL. Further, we found that actvation of astroglia leads to neuroinflammation, which contributes to the rapid progression of the disease. Further, our recent studies have uncovered that autophagy is dysregulated in PPT1-deficient cells causing lysosomal storage. The results of our experiments not only provide insight into a complex mechanism(s) of neurodegeneration in INCL but also identifies several potential therapeutic targets. Publications: Saha A, Lee YC, Zhang Z, Chandra G, Su SB, Mukherjee AB. (2010) Lack of endogenous anti-inflammatory protein in mice enhances colonization of B16F10 melanoma cells in the lungs. J Biol Chem. 285,10822-10831;Kim SJ, Zhang Z, Saha A, Sarkar C, Zhao Z, Xu Y, Mukherjee AB. (2010) Omega-3 and omega-6 fatty acids suppress ER- and oxidative stress in cultured neurons and neuronal progenitor cells from mice lacking PPT1. Neurosci Lett. 479, 292-296;Levin, S.W., Baker, E., Gropman, A., Quezado, Z.M.N., Miao, N., Zhang, Z., Jollands, A., Di Capua, M. and Mukherjee, A.B. (2009) Patients with Infantile Neuronal Ceroid Lipofuscinosis are susceptible to developing Subdural Fluid Collections. Arch. Neurol 66(12):1567-71;Miao N, Levin SW, Baker EH, Caruso RC, Zhang Z, Gropman A, Koziol D, Wesley R, Mukherjee AB, Quezado ZM. (2009) Children with infantile neuronal ceroid lipofuscinosis have an increased risk of hypothermia and bradycardia during anesthesia. Anesth Analg. 109, 372-378;Kim, S.J., Zhang, Z., Lee, Y.C., Sarkar, C., Tsai, P.C., Dye, L. and Mukherjee, A.B. (2008) PPT1-deficiency impairs synaptic vesicle-recycling and regeneration contributing to INCL neuropathology. J. Clin. Invest. 118, 3075-3086.Saha, A., Kim, S.-J., Zhang, Z., Lee, Y.-C., Tsai, P.-C., Soung, J. and Mukherjee, A.B. (2008) Elevated expression of S100B and RAGE mediates neuroinflammation in INCL.FEBS Lett. 582, 3823-3831Chowdhury, B., Zhang, Z., and Mukherjee, A.B. (2008) Uteroglobin interacts with the heparin-binding site of fibronectin and prevents fibronectin-IgA complex formation found in IgA-nephropathy. FEBS Lett. 582, 611-615.Wei, H., Kim, S.J., Zhang, Z., Tsai, P.C., Choi, M.S., Wisniewski, K.E. and Mukherjee, A.B. (2008) ER- and oxidative-stresses are common mediators of cellular death in lysosomal storage disorders: Cytoprotective role of chemical chaperones. Hum. Mol. Genet. 17, 469-477.Zhang, Z., Lee, Y.C., Kim, S.J., Choi, M.S., Tsai, P.C., Saha, A., Wei, H, Xu, Y.J., Zhang, P., Heffer, A. and Mukherjee, A.B. (2007) Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration.Hum Mol Genet. 16, 837-847.Lee, Y.-C., Zhang, Z., Hitomi, E. and Mukherjee, A.B. (2006). Mice lacking uteroglobin are highly susceptible to developing pulmonary fibrosis. FEBS Lett. 580, 4515-4520, 2006. Kim SJ, Zhang Z, Hitomi E, Lee YC and Mukherjee A. B. Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL.Hum Mol Genet. 15, 1826-1834, 2006. Kim SJ, Zhang Z, Lee YC and Mukherjee AB.(2006) Palmitoyl-protein thioesterase-1deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL. Hum Mol Genet. 15,1580-1586;Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Xu Y, Xiao YJ, Zhang P, Heffer A. and Mukherjee AB. (2006). Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. Hum MolGenet. 15, 337-346Wei, H., Kim, S.J., Zhang, Z., Tsai, P.C., Choi, M.S., Wisniewski, K.E. and Mukherjee, A.B. (2008) ER- and oxidative-stresses are common mediators of cellular death in lysosomal storage disorders: Cytoprotective role of chemical chaperones. Hum. Mol. Genet. 17, 469-477.Zhang, Z., Lee, Y.C., Kim, S.J., Choi, M.S., Tsai, P.C., Saha, A., Wei, H, Xu, Y.J., Zhang, P., Heffer, A. and Mukherjee, A.B. (2007) Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration.Hum Mol Genet. 16, 837-847.Lee, Y.-CC., Zhang, Z., Hitomi, E. and Mukherjee, A.B. (2006). Mice lacking uteroglobin are highly susceptible to developing pulmonary fibrosis. FEBS Lett. 580, 4515-4520, 2006. Kim SJ, Zhang Z, Hitomi E, Lee YC and Mukherjee A. B. Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL.Hum Mol Genet. 15, 1826-1834, 2006. Kim SJ, Zhang Z, Lee YC and Mukherjee AB.(2006) Palmitoyl-protein thioesterase-1deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL. Hum Mol Genet. 15,1580-1586, 2006.Zhang Z, Kim SJ, Chowdhury B, Wang J, Lee YC, Tsai PC, Choi M. and Mukherjee AB.Interaction of uteroglobin with lipocalin-1 receptor suppresses cancer cell motility and invasion. Gene. 369, 66-71, 2006.Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Xu Y, Xiao YJ, Zhang P, Heffer A. and Mukherjee AB. (2006). Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. Hum MolGenet. 15, 337-346, 2006.Eisenstein EM, Choi M (2006) Analysis of a uteroglobin gene polymorphism in childhood Henoch-Schonlein purpura. Pediatr Nephrol 21:782-4;Zhang, Z., Kim, S.-J., Lee, Y.-C., Ray, R., Wang, J.-Y., Chowdhury, B., Choi, M.S.,Tsai, P.-C. and Mukherjee, A.B. (2005) Interaction of Uteroglobin with Lipocalin-1 Receptor. Gene. 369:66-71, 2006.Mandal, A.K., Zhang, Z. and Mukherjee, A.B. Yin-yang: balancing act of prostaglandins with opposing functions to regulate inflammation. .J. Immunol, Cutting Edge. 75, 6271-6273, 2005.